2-lower alkyl-2,3-dihydrothieno(3,2-c)quinoline oxides

ABSTRACT

2-LOWER ALKYL - 2,3-DIHYDROTHIENO(3,2-C)QUINOLINE OXIDES AND PHARMACEUTICALLY ACCEPTABLE NON-TOXIC SALTS THEREOF SYNTHESIZED FROM 2-LOWER ALKYL-2,3-HIHYDROTHIENO(3,2C)QUINOLINES OR 3-(2-HALOGENO-LOWER ALKYL)-4-HALOGENOQUINOLINE 1-OXIDES, SHOWING STRONG HYPOTHERMIC ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES WITH LOW TOXICITIES.

United States. Patent Cl 3,663,550 Z-LOWER ALKYL-Z,3-DIHYDROTHIENO[3,2-c] QUINOLINE OXIDES Yasuo Makisumi, Amagasaki-shi, Japan, assignor to Shionogi 8: Co., Ltd., Osaka, Japan No Drawing. Filed Dec. 9, 1969, Ser. No. 883,613 Claims priority, application Japan, Dec. 25, 1968, 43/95,190; Dec. 28, 1968, 44/296, 44/297 Int. Cl. C07d 63/18 US. Cl. 260-283 S 8 Claims ABSTRACT OF THE DISCLOSURE 2-lower alkyl 2,3-dihydrothieno[3,2-c1quinoline oxides and pharmaceutically acceptable non-toxic salts thereof synthesized from 2-lower alkyl-2,3-dihydrothieno[3,2- c]quinlines or 3-(2-halogeno-lower alkyl)-4-halogenoquinoline l-oxides, showing strong hypothermic, analgesic and anti-inflammatory activities with 10W toxicities.

The present invention relates to a 2-lower alkyl-2,3-dihydrothieno[3,2-c]quinoline oxide and pharmaceutically acceptable non-toxic salts thereof. It relates further to processes for their preparations.

The said 2-lower alkyl-2,3-dihydrothieno[3,2-c]quinoline oxide may be represented by the following formula:

1 X- CHgR wherein R is a hydrogen atom or a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl), R' is a hydrogen atom, a halogen atom (e.g. chlorine, bromine, iodine), a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl) or a lower alkoxy group (e.g. methoxy, ethoxy, propoxy, butoxy), Q is a nitrogen atom or a nitroso group and X is a sulfur atom or a sulfinyl group, but Q cannot be a nitrogen atom when X is a sulfur atom.

The thieno[3,2-c]quinoline oxides of Formula I are novel and it has been discovered that they are useful as hypothermic, analgesic and anti-inflammatory agents with low toxicities.

Accordingly, a basic object of the invention is to provide novel thieno[3,2-e]quinoline oxides. Another object of the invention is to provide thieno[3,2-c]quinoline oxides and pharmaceutically acceptable non-toxic salts thereof showing strong hypothermic, analgesic and anti-inflammatory activities. A further object of the invention is to provide a process for preparing the novel thieno[3,2-c] quinoline oxides. These and other objects and the manner in which they are accomplished will become apparent to those conversant with the art from the following description of the general class of compounds and certain specific examples of particular members as well as general and specific method for their production.

The objective compounds of Formula I are Z-lower alkyl-2,3 dihydrothieno[3,2-c]quinoline derivatives of which the sulfur atom or/ and nitrogen atom are oxidized,

2-lower alkyl-2,3-dihydrothieno [3 ,2-c] quinoline l-oxides,

2-lower alkyl-2,3-dihydrothieno [3 ,2-c] quinoline 5-oxides and 2-l0wer alkyl-2,3-dihydrothieno [3,2-c] quinoline 1,5 -dioxides.

3,663,550 Patented May 16, 1972 wherein X is a halogen atom (e.g. chlorine, bromine, iodine) and R and R each has the same significance as designated above.

As illustrative of the objective compounds of Formula I are 2-methyl-2,3-dihydrothieno[ 3,2-c] quinoline l-oxide,

2-ethyl-2,3 -dihydrothieno [3 ,2-c] quinoline l-oxide,

2propyl-2,3 -dihydrothieno [3 ,2-c] quinoline l-oxide,

2 butyl-2,3-dihydrothieno [3 ,2-c] quinoline l-oxide.

2-methyl-7-chloro-2, 3-dihydrothieno [3 ,2-c] quinoline l-oxide,

2-methyl-8-chloro-2,3 -dihydrothieno 3 ,2-c] quinoline l-oxide,

2-methyl-7-bromo-2, 3 -dihydrothieno [3 ,2-c] quinoline l-oxide,

2-methyl-8-io do-2,3 -dihydrothieno [3 ,2-c] quinoline l-oxide,

2-propyl-7-bromo-2,3 -dihydrothieno [3 ,2-c] quinoline 1 -oxide,

2, S-djmethyl-Z, 3 -dihydrothieno 3 ,2-] quinoline l-oxide,

2-methyl-7-ethyl-2, 3 -dihydrothieno [3 ,2-c] quinoline l-oxide,

2-butyl-8-methy1-2,3 -dihydrothieno 3 ,Z-c] quinoline l-oxide,

2-methyl-7-methoxy-2, S-dihydrothieno [3 ,2-c] quinoline l-oxide,

2-methyl-8-methoxy-2,3 -dihydrothieno 3 ,2-c] quinoline l-oxide,

2-ethyl-8-methoxy-2, 3-dihydrothieno [3 ,2-c] quinoline l-oxide,

2-methyl-7-prop oxy-2,3 -dihydrothieno [3 ,2-c] quinoline l-oxide,

2-methyl-2,B-dihydrothieno [3,2-c] quinoline S-oxide,

2-ethyl-2, 3-dihydrothieno [3 ,2-c] quinoline 5 -oxide,

2-propyl-2,3-dihydrothieno [3 ,2-c1quinoline 5-oxide,

2-butyl-2,3-dihydrothieno [3,2-c] quinoline 5-oxide,

2-methyl-7-chlor0-2,3-dihydrothieno 3,2-c] quinoline 5 -0xide,

2-methyl-8-chloro-2,3-dihydrothieno 3,2-c] quinoline 5 -oxide,

2-methyl-8-bromo-2,3 -dihydrothieno [3,2-c] quinoline 5 -oxide,

2-methyl-7-iodo-2,B-dihydrothieno [3,2-c] quinoline S-oxide,

2-butyl-8-chloro-2,3-dihydrothieno [3,2-c] quinoline -oxide,

2,8-dimethyl-2,3-dihydrothieno [3 ,2-c] quinoline 5-oxide,

2-methyl-7-propyl-2,3-dihydrothieno [3 ,2-c] quinoline 5-oxide,

2-propyl-7-methyl-2,3-dihydro thieno [3 ,2-c] quinoline 5-oxide,

2-methyl-7-methoxy-2,3 -dihydro thieno [3 ,2-c] quinoline 5oxide,

Z-methyl-8-methoxy-2,3-dihydrothieno [3 ,2-c] quinoline S-oxide,

2-propyl-7-methoxy-2,3 -dihydrothieno [3 ,2-c] quinoline S-oxide,

2-butyl-8-methoxy-2,3-dihydrothieno 3,2-c] quinoline S-oxide,

2-methy1-2,3-dihydrothieno[3,2-c]quinoline 1,5-dioxide,

2-ethyl-2,3-dihydrothieno [3 ,2-c] quinoline 1,5 -dioxide,

2-propyl-2,3-dihydrothieno 3,2-c] quinoline 1,5 -dioxide,

2-butyl-2,3-dihydrothieno [3 ,2-c] quinoline 1,5 -dioxide,

2-methyl-7-chloro-2,3 -dihydrothieno [3 ,2-c] quinoline 1,5 -dioxide,

2-methyl-8-chloro-2,3-dihydrothieno[3,2-c1quinoline 1,5 -dioxide,

2-methyl-7-bromo-2,3 -dihydro thieno [3 ,2-c] quinoline 1,5 -di0xide,

2-methyl-8-iodo-2,3-dihydrothieno [3,2-c] quinoline 1,5-dioxide,

2-propy1-7-bromo -2,3-dihydrothieno 3 ,2-c] quinoline 1,5 -dioxide,

2,8-dimethyl-2,3 -dihydrothieno 3,2-c] quinoline 1,5-dioxide,

2-methyl-7-ethyl-2,3-dihydrothieno [3,2-c] quinoline 1,5-dioxide,

2-butyl-8-methyl-2,3 -dihydrothieno [3 ,2-c] quinoline 1,5-dioxide,

2-methyl-7-methoxy-2, 3-dihydrothieno 3,2-c] quinoline 1,5-dioxide,

2-methyl-8-methoxy-2,3 -dihydrothieno [3 ,2-c] quinoline 1,5 -dioxide,

2-ethyl-8-methoxy-2,B-dihydrothieno[3,2-c1quinoline 1,5 -dioxide,

2-methyl-7-propoxy-2,S-dihydrothieno [3 ,2-c] quinoline 1,5-dioxide and the like.

According to the present invention, the objective thieno[3,2-c]quinoline oxide of Formula I can be prepared from a thieno[3,2-c1quinoline of Formula II or a 3-(2-halogeno-lower alkyl)-4-halogenoquinoline l-oxide of Formula HI, which is illustrated in detail below, respectively.

(1) Preparation of 2-lower alkyl-2,3-dihydrothieno [3,2-c] quinoline l-oxide [Ia] One of the objective compounds, 2-lower alkyl-2,3- dihydrothieno[3,2-c]quinoline l-oxide [Ia] can be obtained by oxidizing 2-lower alkyl-2,3-dihydrothieno[3,2-c] quinoline [II]. The oxidizing agent employed in the reaction may be selected from those used for oxidizing a sulfide to a sulfoxide, such as hydrogen peroxide, an organic peracid (e.g. performic acid, peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid), periodic acid, a periodate (e.g. sodium periodate, potassium periodate), persulfuric acid, a persulfate (e.g. ammonium persulfate, potassium persulfate), chromic acid, chromic anhydride, a chromate (e.g. sodium bi chromate, potassium bichromate), nitric acid, a hypohalogenous acid (e.g. hypochloric acid, hypobromic acid, hypoiodic acid), a hypohalite (e.g. sodium hypochlorite, sodium hypobromite, sodium hypoiodite), a halogen (e.g. chlorine, bromine, iodine), selenium dioxide, ruthenium tetraoxide, manganese dioxide, lead tetracetate and the like. The oxidation reaction can be carried out at a temperature'ranging from about 0 to about 150 C., but if necessary, the reaction mixture may be cooled when the oxidizing agent is added. As illustrative of the reaction solvents are water, a lower alkanol (e.g. methanol, ethanol propanol), dioxane, tetrahydrofuran, ether, benzene, chloroform, dichloromethane, acetic acid and the like, and a suitable mixture thereof may be also employed.

The products obtainable in the present oxidation reaction and the ratios thereof depend upon the oxidizing agent employed and the reaction conditions under which the reaction is carried out. In the case the reaction is carried out by using an equimolar amount of an organic peracid to the starting compound gives thieno[3,2-c] quinoline l-oxide [Ia] as a main product. The thus produced thieno[3,2-c1quinoline l-oxide [Ia] can be, however, further oxidized to thieno[3,2-c1quino1ine 1,1-dioxide or/and thieno [3,2-c]quino1ine, 1,1,5-trioxide in the presence of the excess organic peracid. There is also produced thieno[3,2-c1quinoline 1,5-dioxide [Ic], but it is only a small amount, since a sulfur atom can be more easily oxidized than a nitrogen atom. Accordingly, for the purpose of the present invention, an equimolar amount of the peracid is to be used. When chromic anhydride, nitric acid or a hypohalite is employed as an oxidizing agent, there is obtained thieno[3,2-c1quinoline l-oxide [Ia] under a mild condition. The oxidation reaction with a periodate, selenium dioxide, manganese dioxide or lead tetracetate is characterized in giving selectively thieno- [3,2-c]quinoline l-oxide [Ia].

The starting compound, thieno[3,2-c1quinoline [II] can be prepared according to the method described in Belgian patent specification No. 694,239. Examples of the starting compound are 2-methyl-2,3-dihydrothieno 3,2-c]quinoline, 2-ethyl-2,3-dihydrothieno[3,2-c1quinoline, 2-propyl-2,3-dihydrothieno 3,2-c] quinoline, 2-butyl-2,3-dihydrothieno [3 ,2-c] quinoline, 2-methyl-7-chloro-2,3-dihydrothieno [3 ,2-c] quinoline, Z-methyl- 8-chloro-2,3 -dihydrothieno [3,2-c] quinoline, 2-methyl-7-bromo-2,3-dihydrothieno 3,2-c] quinoline, 2-methyl-8-iodo-2,3-dihydrothieno [3,2-c] quinoline, 2-propyl-7-bromo-2,3-dihydrothieno 3,2-c] quinoline, 2,8-dimethyl-2,3-dihydrothieno [3 ,2-c] quinoline, 2-methyl-7-ethyl-2,3-dihydrothieno 3,2-c] quinoline, 2-butyl-8-methyl-2,3-dihydrothieno [3 ,2-c] quinoline, 2-methyl-7-methoxy-2,3-dihydrothieno 3 ,2-c] quinoline, 2-methyl-8-methoxy-2,3 -dihydrothieno [3 ,2-c] quinoline, 2-ethyl-8-methoxy-2,3-dihydrothieno [3,2-c] quinoline, 2-methyl-7-propoxy-2,3 -dihydrothieno [3 ,2-c] quinoline and the like.

(2) Preparation of 2-lower alkyl-2,3-dihydrothieno [3,2-c] quinoline S-oxide [Ib] Another objective compound, 2-lower alkyl-2,3-dihydrothieno[3,2-c]quinoline S-oxide [Ib] can be obtained by treating 3 (2 halogeno lower alkyl) 4 halogenoquinoline l-oxide [II] With a mercapto group-introducing agent such as thiourea or an alkali metal hydrogen sulfide (e.g. sodium hydrogen sulfide, potassium hydrogen sulfide). The reaction is carried out in an inert solvent at a temperature ranging from about 30 to about 300 C. As illustrative of the reaction solvent are water, methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol and the like.

The starting compound, 3-(2-halogeno-lower alkyl)- 4-halogenoquinoline l-oxide [II] can be prepared, for instance, by oxidizing a known 3-(2-halogeno-lower alkyl)-4-halogenoquinoline (Andersag et al.; US. Pat. No. 2,650,226) with an organic peracid. Examples of the starting compound are 3-(2-chloropropyl)-4-chloroquinoline l-oxide, 3-(2-bromopropyl)-4-bromoquinoline l-oxide, 3-(2-chlorobutyl)-4-chloroquinoline l-oxide, 3-(2-chloropentyl)-4-ch1oroquinoline l-oxide, 3-(2-chlorohexyl)-4-chloroquinoline l-oxide, 3-(2-bromoheptyl)-4-bromoquinoline l-oxide,

3-(2-chloropropyl)-4,6-dichloroquinoline l-oxide, 3-(2-chloropropyl)-4,7-dichloroquinoline l-oxide, 3-(2-bromopropyl)4-bromo-7-ch1oroquinoline 1oxide, 3-(2-iodopropyl)-4,6-diiodoquinoline 1-oxide, 3-(2-chlorobutyl)-4,7-dichloroquino1ine l-oxide, 3-(2-chloropropyl)4-chloro-fi-methylquinoline l-oxide, 3-(2-bromopropyl)-4 bromo-7-ethylquinoline l-oxide, 3-(2-chlorohexyl) 4-chloro 6methylquinoline l-oxide, 3- (2-chlor0propyl) 4-chloro-7methoxyquinoline l-oxide, 3-(2-iodopropyl)4-iodo-6-methoxyquinoline l-oxide, 3-(2-bromobutyl)4-bromo-6-methoxyquinoline l-oxide, 3-(2-chloropropyl)4-chloro-7-ethoxyquinoline l-oxide, 3 (2-chloropropyl) 4-chloro-6-prop oxyquinoline l-oxide and the like.

(3) Preparation of 2-lower alkyl-2,3-dihydrothieno [3,2-c]quinoline 1,5-dioxide [Ic] 2-l0wer alkyl-2,3-dihydrothieno[3,2-c] quinoline 5-oxide [Ib] obtained according to the above procedure (2) can be converted to the other objective compound, 2-lower alkyl 2,3 dihydrothieno[3,2-c]quinoline 1,5-dioxide [Ic] by an oxidation. The oxidation reaction may be carried out substantially in a similar manner as described in the procedure 1). As an oxidazing agent, there may be exemplified as follows; hydrogen peroxide, an organic peracid (e.g. performic acid, peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid), periodic acid, a periodate (e.g. sodium periodate, potassium periodate), persulfuric acid, a persulfate (e.g. ammonium persulfate, potassium persulfate), chromic acid, chromic anhydride, a chromate (e.g. sodium bichromate, potassium bichromate), nitric acid, a hypohalogenous acid (e.g. hypochloric acid, hypobromic acid, hypoiodic acid), a hypohalorite (e.-g. sodium hypochlorite, sodium hypobromite, sodium hypoiodite), a halogen (e.g. chlorine, bromine, iodine), selenium dioxide, ruthenium tetraoxide, manganese dioxide, lead tetracetate and the like. The treatment of the compound [Ib] with such an oxidizing agent can be carried out at a temperature ranging from about 0 to about 150 C. in a suitable solvent such as water, a lower alkanol (e.g. methanol, ethanol, propanol), dioxane, tetrahydrofuran, ether, benzene, chloroform, dichloromethane, acetic acid and the like, and a mixture thereof.

As mentioned in the above procedure (1), the thus produced thieno[3,2-c]quinoline 1,5-dioxide [Ic] is further oxidized to thieno[3,2-c]quinoline 1,1,5-trioxide according to the oxidizing agent employed and the reaction conditions under which the reaction is carried out. Therefore, in the case of using an organic peracid as the oxidizing agent, an equimolar amount of the peracid is properly to give thieno[3,2-c]quinoline 1,5-dioxide [Ic] with good yield. The oxidation reaction with chromic anhydride, nitric acid or a hypohalite is carried out under a mild condition to avoid the production of thieno[3,2-c] quinoline 1,1,5-trioxide. It is preferred to use the oxidizing agents such as a periodate, selenium dioxide, manganese dioxide, lead tetracetate and the like, which are characterized in giving selectively thieno[3,2-c]quinoline 1,5-dioxide [Ic].

Since the thus produced 2-lower alkyl 2,3 dihydrothieno[3,2c]quinoline oxide [1] is usually a liquid or solid substance which might have a comparatively low melting point, it may be converted, if necessary, into its acid addition salt, for instance, by treating the former with an acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, thiocyanic, carbonic, acetic, propionic, oxalic, citric, tartaric, succinic, salicylic, benzoic or palmitic acid in a suitable solvent such as water, methanol, benzene and toluene. There are the thus produced hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, thiocyanate, carbonate, acetate, propionate, oxalate, citrate, tartrate, succinate, salicylate, benzoate, palmitate and the like.

The 2-lower alkyl 2,3 dihydrothieno[3,2-c1quinoline oxide [I] and its non-toxic salt are useful as hypothermic, analgesic and anti-inflammatory agents. For example, the animal test data of some typical products of the invention are shown in the following table, in contrast with a commercially available and frequently used agent, i.e. aminopyrine.

TABLE Pharmacological Properties of Some Typical 2 LoWer Alkyl 2,3-Dihydrol Toxicity is determined in mice by oral administration.

2 Analgesic activity is determined orally in rats by supression of foot licking caused by Formalin.

Hypothermic activity is presented by depression of the bodily temperature in mice, when treated orally with a dose of 250 mgJkg. of the test compound.

From the test data listed in the table, it is apparent that the five typical products of the invention show remarkably stronger analgesic and hypothermic activities than aminopyrine. Further, the toxicities of those compounds of the invention are as low as that of aminopyrine.

Furthermore, the compounds of the present invention show a marked anti-inflammatory activity, which is as strong as that of phenylbutazone, a commercially available non-steroidal anti-inflammatory agent. F or example, when the inhibition activity against the edema caused by a phlogistic agent, carrageenin, is examined in rats by oral administration of a dose of mg./kg. of the test compound, 2-methyl 2,3 dihydrothieno[3,2-c] quinoline S-oxide hydrochloride, 2-methyl-8-chloro-2,3-dihydrothieno[3,2-c]quinoline 5-oxide hydrochloride, 2-methyl-8- chloro-2,3-dihydrothieno[3,2-c]quinoline 1,5-dioxide, 2,8- dimethyl2,3-dihydrothieno[3,2-c]quinoline l-oxide and aminopyrine show 40.5%, 41.8%, 46.4%, 42.9% and 43.3% inhibitions, respectively.

The other 2-lower alkyl-2,3-dihydrothieno[3,2-c]quinoline oxides and non-toxic acid addition salts thereof provided by the present invention also show similarly excellent pharmacological properties. Accordingly, the compounds of Formula I and pharmaceutically acceptable non-toxic salt thereof are useful as hypothermic, analgesic and auti-inflammatory agents of a low toxicity, which can be administered in dosage unit form, as carried by a suitable pharmaceutical carrier, to human beings particularly for relieving fever, pain and/or inflammation. Administration is advantageously effected orally in the form of conventionally prepared tablets or the like. Each tablet, or other per se conventional administration form, may contain e.g. 50 to 200 milligrams of active compound according to the invention and medication is continued at intervals prescribed e.g. by the attending physician until relief is attained.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for the purpose of illustration only and not of limitation.

In the examples which follow, parts by weight bear the same relation to parts by volume as do grams to millilitres. Temperatures are set forth in degrees centigrade. The abbreviations have conventional significances.

7 EXAMPLE 1 S os-s s (a) To a solution of 2-methyl-2,3-dihydrothieno[3,2- c]quinoline (2.01 parts by weight) in methanol (80 parts by volume) is added dropwise another solution of sodium periodate (2.3 parts by weight) in water (40 parts by volume) while stirring and ice cooling, and the mixture is allowed to stand overnight at a room temperature. After removal of the precipitated sodium iodate by filtration, the filtrate is concentrated under reduced pressure and the residue is extracted with chloroform. The extract is washed with Water, dried over anhydrous magnesium sulfate and evaporated. The oily residue is chromatographed on alumine and eluted with benzene-chloroform to give Z-methyl-2,3-dihydrothieno[3,2-c]quinoline l-oxide (1.89 parts by weight) as colorless plates melting at 103 to 104 C., when recrystallized from benzene-petroleum ether.

Analysis.Calcd. for C H NOS (percent): C, 66.33; H, 5.10; N, 6.40. Found (percent): C, 66.15; H, 5.11; N, 6.47.

(b) To a solution of 2-methyl-2,3-dihydrothieno[3,2- c]quinoline (1.0 part by weight) in ethanol parts by volume) is added 30% hydrogen peroxide (0.6 part by weight) and the mixture is refluxed for 2 hours on a water bath. After removal of ethanol under reduced pressure, the residue is diluted with a little amount of water and extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. The oily residue is chromatographed on alumina and eluted with chloroform to give 2-methyl-2,3-dihydrothieno[3,2-c]quinoline l-oxide (0.3 part by weight) being identical with the authentic sample.

(0) To a solution of 2-methyl-2,3-dihydrothieno[3,2- clquinoline (2.0 parts by weight) in dichloromethane (20 parts by volume) is added dropwise another solution of 3-chloroperbenzoic acid (2.36 parts by weight, purity; 82.5%) in dichloromethane (30 parts by volume) while stirring and ice cooling, and the mixture is stirred at a room temperature for 1 hour. The reaction mixture is chromatographed on alumina and 3-ch'1oroperbenzoic acid is removed by elution with dichloromethane. The subsequent eluate with benzene-chloroform gives 2-methyl-2,3- dihydrothieno[3,2-c]quinoline l-oxide (1.95 parts by weight) being identical with the authentic sample. Further, there are also produced the following two compounds in the reaction.

(1) 2-methy1-2,3-dihydrothieno[3,2-c]quinoline 1,1-dioxide (0.16 part by weight), colorless pillars melting at 126 to 127 C. (recrystallized from benzene).

Analysis.-Calcd. for C H NO S (percent): C, 61.77; H, 4.75; N, 6.00. Found (percent): C, 61.87; H, 4.62; N, 5.97.

(2) 2-methyl-2,3-dihydrothieno[3,2-c]quinoline 1,5-dioxide (0.05 part by Weight), colorless prisms melting at 148 to 150 C. (recrystallized from benzene).

Analysis.-Calcd. for C H NO S (percent): C, 61.77; H, 4.75; N, 6.00. Found (percent): C, 62.02; H, 4.67; N,

To a solution of 2-ethyl-2,3-dihydrothieno[3,2-c]quinoline (2.64 parts by weight) in methanol .(100 parts by volume) is added dropwise another solution of sodium periodate (2.73 parts by weight) in water (50 parts by EXAMPLE 2 8 volume), while stirring and ice cooling. The reaction is carried out in a similar manner to Example 1(a) to give 2-ethyl-2,3-dihydrothieno[3,2-c]quinoline l-oxide (2.348 parts by weight) as an oily substance.

The hydrochloride is constituted by crystals melting at 161 to 162 C., when recrystallized from methanolacetone.

Analysis.-Calcd. for C H NOS-HCl .(percent): C, 58.30; H, 5.27; N, 5.23; S, 11.98. Found (percent): C, 58.25; H, 5.30; N, 5.25; S, 11.97.

EXAMPLE 3 EXAMPLE 4 CH on s 3 Ohs 3 To a solution of 2-methyl-7-chloro-2,3-dihydrothieno [3,2-c]quinoline (2.7 parts by weight) in methanol parts by volume) is added dropwise another solution of sodium periodate (2.7 parts by weight) in water .(50 parts by volume) while stirring and ice cooling. The reaction is carried out in a similar manner to Example 1(a) to give 2-methyl-7-chloro-2,3-dihydrothieno[3,2-c] quinoline l-oxide as crystals melting at to 131 C., when recrystallized from benzene-petroleum ether.

Analysis.Calcd. for C H NOSCI (percent): C, 57.26; H, 3.98; N, 5.57. Found ,(percent): C, 57.47; H, 4.02; N, 5.45.

EXAMPLE 5 To a solution of 2-methyl-8-chloro-2,3-dihydrothieno [3,2-c]quinoline (2.67 parts by weight) in methanol (100 parts by volume) is added dropwise another solution of sodium periodate (2.67 parts by weight) in water (50 parts by volume) while stirring and ice cooling. The reaction is carried out in a similar manner to Example 1(a) to give 2-methyl-8-chloro-2,3-dihydrothieno[3,2-c]quinoline l-oxide (2.585 parts by weight) as crystals melting at to 176 0., when recrystallized from benzene-petroleum ether.

Analysis.-Calcd. for C H NOSCl .(percent): C, 57.26; H, 3.98; N, 5.57. Found (percent): C, 57.50; H, 4.11; N, 5.50.

9 EXAMPLE 6 s CH: obs 2H CH CH To a solution of 2-methyl-8-methoxy-2,3-dihydrothieno [3,2-c1quinoline (2.31 parts by weight) in methanol (80 parts by volume) isadded dropwise another solution of sodium periodate (2.3 parts by weight) in water (40 parts by volume) while stirring and ice cooling. The reaction is carried out in a similar manner to Example 1(a) to give 2-methyl 8 methoxy-2,3-dihydrothieno[3,2-c] quinoline l-oxide (2.35 parts by weight) as colorless prisms melting at 104 to 105 C., when recrystallized from benzene-petroleum ether.

Analysis.Calcd. for C H NO S (percent): C, 63.13; H, 5.30; N, 5.66. Found (percent): C, 63.05; H, 5.47;

EXAMPLE 8 c1 c1 5 m3 i ,CHZHCH3 N/ i. t

A solution of 3-(2-chloropropyl)-4-chloroquinoline 1- oxide (4.6 parts by weight) and sodium hydrogen sulfide (3.02 parts by weight) in anhydrous ethanol (75 parts by volume) is heated at 30 to 40 C. for 1 hour and refluxed for 2 hours. After cooling, the precipitated sodium chloride is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with chloroform, then the extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on alumina and eluted with benzene-chloroform to give 2-methyl-2,3- dihydrothieno[3,2-c] quinoline 5-oxide (3.307 parts by weight) as an oily substance.

The hydrochloride is constituted by yellow pillars melting at 150 to 152 C., when recrystallized from methanolacetone.

Analysis.'Calcd. for C H NOS-HCl (percent): C, 56.79; H, 4.76; N, 5.52. Found (percent): C, 56.57; H, 4.93; N, 5.29.

The picrate is constituted by crystals melting at 181 to 183 C., when recrystallized from ethanol.

Analysis.--Calcd. for C H NOS-C H N O (percent): C, 48.42; H, 3.16; (N, 12.55. Found (percent): C, 48.39; H, 3.31; N, 12.74.

EXAMPLE 9 CH 01 n s 3 C1 CH CHCH Cl A solution of 3-(2-chloropropyl)-4,6-dichloroquinoline l-oxide (12 parts by weight) and sodium hydrogen sulfide (4.63 parts by weight) in anhydrous ethanol (200 parts by volume) is heated at 40 C. for 1 hour and further refluxed for 2 hours. The reaction mixture is treated in a similar manner to Example 8 and purified by chromatography on alumina. The product is eluted with chloroform and recrystallized from benzene-petroleum ether to give 2-methyl-8-chloro 2,3 dihydrothieno[3,2-c]quinoline 5-oxide (9.66 parts by weight) as yellow pillars melting at 154 to 155 C.

Analysis.Calcd. for C H NOSCl (percent): C, 57.25; H, 4.00; N, 5.56. Found (percent): C, 57.35; H, 4.01; N, 5.65.

The hydrochloride is constituted by colorless pillars melting at to 162 C., when recrystallized from acetone-methanol.

Analysis.Calcd. for C H NOSCl-HCl (percent): C, 50.00; H, 3.84; N, 4.86. Found (percent): C, 50.07; H, 3.89; N, 4.67.

EXAMPLE 10 c1 c1 3 3 CH3 CHZCHCH'3 CH3 N/ o i,

A solution of 3-(2-chloropropyl)-4-chloro-6-methylquinoline l-oxide (32.5 parts by weight) and sodium hydrogen sulfide (14 parts by weight) in anhydrous ethanol (500 parts by volume) is heated at 40 C. for 1 hour and further refluxed for 2.5 hours. After cooling, the precipitated sodium chloride is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is diluted with water, made alkaline with sodium carbonate and extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. The crystalline residue is recrystallized from benzene-petroleum ether to give 2,8-dimethyl- 2,3-dihydrothieno[3,2-c]quinoline 5-oxide (27.1 parts by weight) as colorless pillars melting at 162.5 to 164 C.

AnalysfS.-Calcd. for C H NOS (percent): C, 67.50; H, 5.66; N, 6.06. Found (percent): C, 67.67; H, 5.62; N, 6.08.

The hydrochloride is constituted by yellow plates melting at C., when recrystallized from acetonemethanol.

Analysis.-Calcd. for C H NOS-HCI (percent): C, 58.31; H, 5.27; N, 5.23. Found (percent): C, 58.29; H, 5.28; N, 5.43.

EXAMPLE 11 A solution of 3-(2-chloropropyl)-4-chloro-6-methoxyquinoline l-oxide (16.4 parts by weight) and sodium hydrogen sulfide (8.4 parts by weight) in anhydrous ethanol (250 parts by volume) is heated at 40 C. for 1 hour and further refluxed for 2.5 hours. The reaction mixture is treated in a similar manner to Example 10 and purified by recrystallization from benzene to give 2-methyl-8- methoxy 2,3 dihydrothieno[3,2-c]quinoline -oxide (12.39 parts by weight) as yellow needles melting at 177.5 to 179 C.

AnaIysis.--Calcd. for C H NO S (percent): C, 63.14; H, 5.30; N, 5.66. Found (percent): C, 63.37; H, 5.25; N, 5.43.

The hydrochloride is constituted by crystals melting at 172 C., when recrystallized from acetone.

Analysis.--Calcd. for C H NO S-HCl (percent): C, 55.02; H, 4.97; N, 4.94. Found (percent): C, 54.95; H, 4.90; N, 4.70.

EXAMPLE 12 c 11 c1 (11 is 4 9 ca cac u N/ L L o o A solution of 3-(2-chlorohexyl)-4-chloroquinoline 1- oxide (4.4 parts by weight) and thiourea (1.23 parts by weight) in methanol (30 parts by volume) is heated for 1 hour under refluxing. After removal of the solvent, the residue is diluted with water, made alkaline with sodium carbonate and extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. Chromatographic purification gives 2-butyl-2,3-dihydrothieno[3,2-c]quinoline 5- oxide (2.47 parts by weight) as an oily substance.

The hydrochloride is constituted by crystals melting at 116 to 119 0., when recrystallized from acetone-benzene.

Analysis.Calcd. for C H NOS-HCl (percent): C, 60.90; H, 6.13; N, 4.74; S, 10.84. Found (percent): C, 60.94; H, 6.23; N, 4.86; S, 10.83.

The picrate is constituted by crystals melting at 132 to 133 0., when recrystallized from ethanol-dichloromethane.

Analysis.-Calcd. for C15H1qNOS'C H3N307 (PCT- cent): C, 51.63; H, 4.13; N, 11.47; S, 6.56. Found (percent): C, 51.74; H, 4.24; N, 11.47; S, 6.85.

In the reaction, there is also obtained 2-amino-4-butyl- 4,5,6,7-tetrahydro 1,3 thiazepino[6,7-c1quinoline-6- one (0.418 part by weight) as crystals melting at 173 to 175 C., when recrystallized from ethanol-dichloromethane.

Analysis.-Calcd. for C H N OS (percent): C, 63.76; H, 6.35; N, 13.94; S, 10.64. Found (percent): C, 63.87; H, 6.50; N, 14.01; S, 10.66.

To a solution of 2-methyl-2,3-dihydrothieno[3,2-c] quinoline 5-oxide (4.34 parts by weight) in methanol (200 parts by volume) is added another solution of sodium periodate (4.71 parts by weight) in water (100 parts by volume) while stirring and ice cooling. The resulting mixture is stirred at a room temperature for 1 hour and allowed to stand overnight. After removal of the precipitated sodium iodate by filtration, the filtrate is concentrated under reduced pressure. The residue is extracted With chloroform and the extract is washed with water, dried over anhydrous magnesium sulfate and evaporated. Recrystallization from benzene gives 2-methyl-2,3-dihydro thieno[3,2-c] quinoline 1,5-dioxide (3.68 parts by weight) as colorless prisms melting at 148 to 150 C.

Analysis.Calcd. for C H NO S (percent): C, 61.77; H, 4.75; N, 6.00. Found (percent): C, 62.02; H, 4.67; N, 6.04.

1 2 EXAMPLE 14 s 3 o-s To a solution of 2-methyl-8-chloro-2,3-dihydrothieno [3,2-c]quinoline 5-oxide (5 parts by weight) in methanol (200 parts by volume) is added dropwise another solution of sodium periodate (4.686 parts by weight) in water (100 parts by volume) while stirring and ice cooling. Working up in a similar manner to Example 13, there is obtained 2-methyl-8-chloro-2,3-dihydrothieno [3,2-c] quinoline 1,5-dioxide (4.91 parts by weight) as colorless pillars melting at 178 C., when recrystallized from benzene.

Analysis.Calcd. for C H NO SCl (percent): C, 53.83; H, 3.76; N, 5.23; S, 11.97. Found (percent): C, 53.67; H, 3.82; N, 5.20; S, 11.98.

EXAMPLE 15 ca Gil S 3 oc-s 3 on on N L o 0 To a solution of 2,8-dimethyl-2,3-dihydrothieno[3,2-c] quinoline 5-oxide (3 parts by weight) in methanol (100 parts by volume) is added dropwise another solution of sodium periodate (3.1 parts by weight) in water (50 parts by volume) While stirring and ice cooling. Working up in a similar manner to Example 13, there is obtained 2,8- dimethyl-2,3-dihydrothieno[3,2-c]quinoline 1,5 dioxide (3.03 parts by weight) as colorless pillars melting at 154.5 to 156.5" C., when recrystallized from benzene-petroleum ether.

Analysis.-Calcd. for C H NO S (percent): C, 63.14; H, 5.30; N, 5.66. Found (percent): C, 63.21; H, 5.27; N, 5.57.

EXAMPLE 16 S cg} g 3 (aged c11 0 i i t is To a solution of 2-methyl-8-methoxy-2,3-dihydrothieno [3,2-c]quinoline 5-oxide (3 parts by weight) in methanol parts by volume) is added dropwise another solution of sodium periodate (2.87 parts by weight) in water (50 parts by volume) while stirring and ice cooling. Working up in a similar manner to Example 13, there is obtained 2 methyl 8-methoXy-2,3-dihydrothieno[3,2-c] quinoline 1,5-dioxide (2.98 parts by weight) as colorless pillars melting at 161 to 162 C., when recrystallized from benzene.

Analysis.--Calcd. for C I-1 N0 8 (percent): C, 59.30; H, 4.98; N, 5.32. Found (percent): C, 59.10; H, 4.99; N, 5.03.

What is claimed is:

1. A compound of the formula OPS CHzR wherein R is a member selected from the group consisting of hydrogen atom and lower alkyl group containing from 1 to 5 carbon atoms and R is a member selected from the group consisting of hydrogen atom, halogen atom, lower alkyl group containing from 1 to 5 carbon atoms and lower alkoxy group containing from 1 to 4 carbon atoms.

2. The compound according to claim 1, namely 2-methyl-2,3-dihydrothieno [3,2-c] quinoline l-oxide.

3. The compound according to claim 1, namely 2- ethyl-2,3-dihydrothieno 3,2-c] quinoline l-oxide.

4. The compound according to claim 1, namely 2-butyl- 2,3-dihydrothieno[3,2-c]quinoline l-oxide.

5. The compound according to claim 1, namely 2- methyl-7-chloro-2,3-dihydrothieno[3,2-c1quinoline 1 oxide.

6. The compound according to claim 1, namely 2- methyl-8-chloro-2,3 dihydrothieno[3.2 c]quinoline 1- oxide.

7. The compound according to claim 1, namely 2,8- dimethyl 2,3 dihydrothieno[3,2-c]quinoline 1 oxide.

14 8. The compound according to claim 1, namely Z-methyl 8 methoxy 2,3 dihydrothieno[3,2-c1quinoline l-oxide.

References Cited UNITED STATES PATENTS 2,650,226 8/1953 Andersag et a1 260-288 X 2,650,227 8/1953 Timmler et a1 260288 3,532,700 10/1970 Makisumi 260-283 3,047,579 7/1962 Witman 260289 OTHER REFERENCES Makisumi et al.: Chem. Abstr., vol. 70, col. 106488a (1969) (abstracting Japan 69/3,825 (February 1969)).

Kobayashi et al.: Chem. Abstr., vol. 59, col. 5l44d (1963).

DONALD G. DAUS, Primary Examiner U.S. Cl. X.R.

260283 R, 286 R, 289 R, 999 

